Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective To deeply understand the anatomical basis of temporomandibular joint disorders,and explore and master the pathological characteristics of anterior displacement of temporomandibular joint disc through cadaveric dissection and 3D printing technology.Methods By dissecting the temporomandibular joints of 40 head and neck specimens,the bilateral structures of the temporomandibular joints were measured to obtain condyle and articular disc data.3D modeling was carried out using 3ds Max software and printed out a model of temporomandibular joint.The pathological model of the anterior disc displacement with reduction(ADDwR)was simulated by adjusting the opening degree,the position of the articular disk,and the position of the condyle of the model.Results The precise data of the right and left temporomandibular joint discs and condyle were successfully obtained by dissection and measurement.The thickness of the anterior band of left temporomandibular joint discs was(2.02±0.57)mm,the thickness of the middle band was(1.46±0.33)mm,the thickness of the posterior band was(3.00±0.46)mm,the anterior-posterior diameter was(9.60±0.72)mm,and the internal-external diameter was(17.73±0.84)mm.While the thickness of the anterior band of right temporomandibular joint discs was(1.84±0.35)mm,and the thickness of the middle band was(1.43±0.28)mm,the thickness of posterior band was(3.08±0.49)mm,the anterior-posterior diameter was(9.30±0.88)mm,and the internal-external diameter was(17.38±1.10)mm.The internal-external diameter of the left temporomandibular joint condyle was(18.97±0.41)mm,and the anterior-posterior diameter was(8.56±0.43)mm;the internal-external diameter of the right temporomandibular joint condyle was(18.86±0.75)mm,and the anterior-posterior diameter was(8.40±0.30)mm.The standard temporomandibular joint model was printed out by the measured data.The model was utilized to simulate the physiological state of temporomandibular joint under normal conditions,as well as the three pathological states of closed mouth,closed mouth to open mouth,and open mouth in the case of ADDwR.Conclusion The temporomandibular joint model can more intuitively present the changes of anatomical structure in reversible temporoman-dibular joint disorders,which is helpful for understanding and mastering the different classification of this disease.

Objective To deeply understand the anatomical basis of temporomandibular joint disorders,and explore and master the pathological characteristics of anterior displacement of temporomandibular joint disc through cadaveric dissection and 3D printing technology.Methods By dissecting the temporomandibular joints of 40 head and neck specimens,the bilateral structures of the temporomandibular joints were measured to obtain condyle and articular disc data.3D modeling was carried out using 3ds Max software and printed out a model of temporomandibular joint.The pathological model of the anterior disc displacement with reduction(ADDwR)was simulated by adjusting the opening degree,the position of the articular disk,and the position of the condyle of the model.Results The precise data of the right and left temporomandibular joint discs and condyle were successfully obtained by dissection and measurement.The thickness of the anterior band of left temporomandibular joint discs was(2.02±0.57)mm,the thickness of the middle band was(1.46±0.33)mm,the thickness of the posterior band was(3.00±0.46)mm,the anterior-posterior diameter was(9.60±0.72)mm,and the internal-external diameter was(17.73±0.84)mm.While the thickness of the anterior band of right temporomandibular joint discs was(1.84±0.35)mm,and the thickness of the middle band was(1.43±0.28)mm,the thickness of posterior band was(3.08±0.49)mm,the anterior-posterior diameter was(9.30±0.88)mm,and the internal-external diameter was(17.38±1.10)mm.The internal-external diameter of the left temporomandibular joint condyle was(18.97±0.41)mm,and the anterior-posterior diameter was(8.56±0.43)mm;the internal-external diameter of the right temporomandibular joint condyle was(18.86±0.75)mm,and the anterior-posterior diameter was(8.40±0.30)mm.The standard temporomandibular joint model was printed out by the measured data.The model was utilized to simulate the physiological state of temporomandibular joint under normal conditions,as well as the three pathological states of closed mouth,closed mouth to open mouth,and open mouth in the case of ADDwR.Conclusion The temporomandibular joint model can more intuitively present the changes of anatomical structure in reversible temporoman-dibular joint disorders,which is helpful for understanding and mastering the different classification of this disease.

Objective:To investigate the genetic causal relationship of leukocyte telomere length(LTL)with prostatitis,orchi-tis and epididymitis by two-sample Mendelian randomization(MR).Methods:Using LTL as the exposure factor and prostatitis,or-chitis and epididymitis as outcome factors,we mined the Database of Genome-Wide Association Studies(GWAS).Then,we analyzed the causal relationship of LTL with prostatitis,orchitis and epididymitis by Mendelian randomization using inverse variance weighting(IVW)as the main method and weighted median and MR-Egger regression as auxiliary methods,determined the horizontal multiplicity by MR-Egger intercept test,and conducted sensitivity analysis using the leaving-one-out method.Results:A total of 121 related sin-gle nucleotide polymorphisms(SNPs)were identified in this study.IVW showed LTL to be a risk factor for prostatitis(OR=1.383,95％CI:1.044-1.832,P=0.024),and for orchitis and epididymitis as well(OR=1.770,95％CI:1.275-2.456,P=0.000 6).Conclusion:Genetic evidence from Mendelian randomized analysis indicates that shortening of LTL reduces the risk of prostatitis,orchitis and epididymitis.

Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

BACKGROUND: Ventricular remodeling after acute anterior wall ST-segment elevation myocardial infarction (AAMI) is an important factor in occurrence of heart failure which additionally results in poor prognosis. Therefore, the treatment of ventricular remodeling needs to be further optimized. Compound Danshen Dripping Pills (CDDP), a traditional Chinese medicine, exerts a protective effect on microcirculatory disturbance caused by ischemia-reperfusion injury and attenuates ventricular remodeling after myocardial infarction. OBJECTIVE: This study is designed to evaluate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function after AAMI on a larger scale. METHODS: This study is a multi-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The total of 268 patients with AAMI after primary percutaneous coronary intervention (pPCI) will be randomly assigned 1:1 to the CDDP group (n=134) and control group (n=134) with a follow-up of 48 weeks. Both groups will be treated with standard therapy of ST-segment elevation myocardial infarction (STEMI), with the CDDP group administrating 20 tablets of CDDP before pPCI and 10 tablets 3 times daily after pPCI, and the control group treated with a placebo simultaneously. The primary endpoint is 48-week echocardiographic outcomes including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI). The secondary endpoint includes the change in N terminal pro-B-type natriuretic peptide (NT-proBNP) level, arrhythmias, and cardiovascular events (death, cardiac arrest, or cardiopulmonary resuscitation, rehospitalization due to heart failure or angina pectoris, deterioration of cardiac function, and stroke). Investigators and patients are both blinded to the allocated treatment. DISCUSSION This prospective study will investigate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function in patients undergoing pPCI for a first AAMI. Patients in the CDDP group will be compared with those in the control group. If certified to be effective, CDDP treatment in AAMI will probably be advised on a larger scale. (Trial registration No. NCT05000411).
Humans ; ST Elevation Myocardial Infarction/therapy* ; Stroke Volume ; Ventricular Remodeling ; Prospective Studies ; Microcirculation ; Ventricular Function, Left ; Myocardial Infarction/etiology* ; Treatment Outcome ; Percutaneous Coronary Intervention/adverse effects* ; Heart Failure/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic

The process of semen collection plays a key role in the quality of semen specimens. However, the association between semen collection time and semen quality is still unclear. In this study, ejaculates by masturbation from 746 subfertile men or healthy men who underwent semen analysis were examined. The median (interquartile range) semen collection time for all participants was 7.0 (5.0-11.0) min, and the median time taken for semen collection was lower in healthy men than that in subfertile men (6.0 min vs 7.0 min). An increase in the time required to produce semen samples was associated with poorer semen quality. Among those undergoing assisted reproductive technology (ART), the miscarriage rate was positively correlated with the semen collection time. After adjusting for confounders, the highest quartile (Q4) of collection time was negatively associated with semen volume and sperm concentration. A longer time to produce semen samples (Q3 and Q4) was negatively correlated with progressive and total sperm motility. In addition, there was a significant negative linear association between the semen collection time and the sperm morphology. Higher risks of asthenozoospermia (adjusted odds ratio [OR] = 2.06, 95% confidence interval [CI]: 1.31-3.25, P = 0.002) and teratozoospermia (adjusted OR = 1.98, 95% CI: 1.10-3.55, P = 0.02) were observed in Q3 than those in Q1. Our results indicate that a higher risk of abnormal semen parameter values was associated with an increase in time for semen collection, which may be related to male fertility through its association with semen quality.
Male ; Humans ; Semen Analysis ; Semen ; Sperm Motility ; Sperm Count ; Asthenozoospermia ; Spermatozoa

Objective: To explore the feasibility of endoscopic hand-suturing (EHS) for rectal defects closure after endoscopic submucosal dissection (ESD), and the clinical practicability of EHS combined with titanium clips. Methods: This is a prospective study performed by two experienced endoscopists from the Cancer Hospital, Chinese Academy of Medical Sciences who had received EHS training in sixporcine gastric ESD defects in vivo before the study. From December 2022 to February 2022, 20 patients with rectal mucosal lesions or submucosal diseases underwent ESD. Then EHS combined with titanium clips was adopted to close the rectal ESD defects. Specifically, we first sutured the defects as much as possible through EHS, then use titanium clips to fix the tail of the suture, and finally use additional titanium clips to close the residual parts of the defects that cannot be sutured. The main observational indicators were complete closure of the wound and delayed bleeding within one month after surgery. Results: In the 20 rectal cases, the size of defects ranged from 2.2 to 3.6 cm, with a median of 2.7 cm. All cases achieved complete closure without delayed bleeding, of which 12 (60.0%) were completely sutured with EHS and 8 (40.0%) required additional titanium clips to achieve complete closure after suturing. Conclusion: EHS technique is feasible and safe for rectum. EHS combined with titanium clips can also effectively close the rectal ESD defects, prevent postoperative delayed bleeding, and may be easier to be implemented in clinical practice.
Humans ; Rectum/surgery* ; Endoscopic Mucosal Resection/methods* ; Pilot Projects ; Titanium ; Prospective Studies ; Surgical Instruments ; Sutures ; Treatment Outcome ; Retrospective Studies

Objective: To explore the feasibility of endoscopic hand-suturing (EHS) for rectal defects closure after endoscopic submucosal dissection (ESD), and the clinical practicability of EHS combined with titanium clips. Methods: This is a prospective study performed by two experienced endoscopists from the Cancer Hospital, Chinese Academy of Medical Sciences who had received EHS training in sixporcine gastric ESD defects in vivo before the study. From December 2022 to February 2022, 20 patients with rectal mucosal lesions or submucosal diseases underwent ESD. Then EHS combined with titanium clips was adopted to close the rectal ESD defects. Specifically, we first sutured the defects as much as possible through EHS, then use titanium clips to fix the tail of the suture, and finally use additional titanium clips to close the residual parts of the defects that cannot be sutured. The main observational indicators were complete closure of the wound and delayed bleeding within one month after surgery. Results: In the 20 rectal cases, the size of defects ranged from 2.2 to 3.6 cm, with a median of 2.7 cm. All cases achieved complete closure without delayed bleeding, of which 12 (60.0%) were completely sutured with EHS and 8 (40.0%) required additional titanium clips to achieve complete closure after suturing. Conclusion: EHS technique is feasible and safe for rectum. EHS combined with titanium clips can also effectively close the rectal ESD defects, prevent postoperative delayed bleeding, and may be easier to be implemented in clinical practice.
Humans ; Rectum/surgery* ; Endoscopic Mucosal Resection/methods* ; Pilot Projects ; Titanium ; Prospective Studies ; Surgical Instruments ; Sutures ; Treatment Outcome ; Retrospective Studies

Objective: To construct the diagnostic model of superficial esophageal squamous cell carcinoma (ESCC) and precancerous lesions in endoscopic images based on the YOLOv5l model by using deep learning method of artificial intelligence to improve the diagnosis of early ESCC and precancerous lesions under endoscopy. Methods: 13, 009 endoscopic esophageal images of white light imaging (WLI), narrow band imaging (NBI) and lugol chromoendoscopy (LCE) were collected from June 2019 to July 2021 from 1, 126 patients at the Cancer Hospital, Chinese Academy of Medical Sciences, including low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, ESCC limited to the mucosal layer, benign esophageal lesions and normal esophagus. By computerized random function method, the images were divided into a training set (11, 547 images from 1, 025 patients) and a validation set (1, 462 images from 101 patients). The YOLOv5l model was trained and constructed with the training set, and the model was validated with the validation set, while the validation set was diagnosed by two senior and two junior endoscopists, respectively, to compare the diagnostic results of YOLOv5l model and those of the endoscopists. Results: In the validation set, the accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the YOLOv5l model in diagnosing early ESCC and precancerous lesions in the WLI, NBI and LCE modes were 96.9%, 87.9%, 98.3%, 88.8%, 98.1%, and 98.6%, 89.3%, 99.5%, 94.4%, 98.2%, and 93.0%, 77.5%, 98.0%, 92.6%, 93.1%, respectively. The accuracy in the NBI model was higher than that in the WLI model (P<0.05) and lower than that in the LCE model (P<0.05). The diagnostic accuracies of YOLOv5l model in the WLI, NBI and LCE modes for the early ESCC and precancerous lesions were similar to those of the 2 senior endoscopists (96.9%, 98.8%, 94.3%, and 97.5%, 99.6%, 91.9%, respectively; P>0.05), but significantly higher than those of the 2 junior endoscopists (84.7%, 92.9%, 81.6% and 88.3%, 91.9%, 81.2%, respectively; P<0.05). Conclusion: The constructed YOLOv5l model has high accuracy in diagnosing early ESCC and precancerous lesions in endoscopic WLI, NBI and LCE modes, which can assist junior endoscopists to improve diagnosis and reduce missed diagnoses.
Artificial Intelligence ; Endoscopy/methods* ; Esophageal Neoplasms/pathology* ; Esophageal Squamous Cell Carcinoma/diagnostic imaging* ; Humans ; Narrow Band Imaging ; Precancerous Conditions/diagnostic imaging* ; Sensitivity and Specificity